p53 activation suppresses malic enzyme expression and leads to senescence in pre-cancerous cells

Published on January 16, 2013 at 12:48 AM · No Comments

It is perhaps impossible to overstate the importance of the tumor suppressor gene p53. It is the single most frequently mutated gene in human tumors. p53 keeps pre-cancerous cells in check by causing cells, among other things, to become senescent - aging at the cellular level. Loss of p53 causes cells to ignore the cellular signals that would normally make mutant or damaged cells die or stop growing.

In short, the p53 pathway is an obvious and attractive target for drug developers. But that strategy has so far proven difficult, as most p53 regulatory proteins operate via protein-protein interactions, which make for poor drug targets, as opposed to ones based on enzymes.

Now, a team of researchers from the Perelman School of Medicine, University of Pennsylvania, has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates.

As Xiaolu Yang, PhD, professor of Cancer Biology and investigator in Penn's Abramson Family Cancer Research Institute, and his team describe in an advance online Nature publication, p53 participates in a molecular feedback circuit with malic enzymes, thereby showing that p53 activity is also involved in regulating metabolism.(The Yang lab identified p53's role in glucose metabolism in the past.)

The new findings, Yang says, suggest that p53 acts as a molecular sensor of metabolic stress and explains how metabolic stress can lead to senescence in cells.

"We uncovered an important regulatory mechanism for p53 as well as an effector mechanism for p53," Yang says.

Significantly, the findings also identify malic enzymes as novel and potentially useful pharmaceutical targets for anticancer therapy, as well as possible mediators of the normal aging process - though neither possibility was actually addressed in the current study.

As cells become damaged and precancerous, the p53 protein prevents those cells from continuing towards becoming tumors by causing the cells to senesce. Metabolic cues also regulate senescence, but the molecular relays coupling those two processes -- senescence and metabolism -- remained unknown.

Yang and his team, including postdoctoral fellows Peng Jiang, PhD, and Wenjing Du, PhD, decided to test if a pair of enzymes, malic enzyme 1 and malic enzyme 2 (ME1 and ME2), could be involved. Malic enzymes recycle malate - an intermediate molecule - back into an end-product of glycolysis - pyruvate - storing energy in the process. Malic enzymes are important for adjusting metabolic flux to suit proliferating cells' demands for energy and biosynthesis. Thus, these two enzymes are attuned to the energy and proliferative state of the cell.

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